1. Field of the Invention
This invention relates to a stabilized dry preparation of S-adenosyl-L-methionine or a low-toxicity salt thereof and a process for production of the preparations.
2. Description of the Prior Art
S-adenosyl-L-methionine (hereinafter referred to as SAM) exists in numerous kinds of organisms such as animals, plants and microorganisms in the natural world, and is a psysiologically active substance which plays an important role as a methyl group donor of methylation reaction by way of various transmethylases in living organisms. For example, SAM is an indispensable substance which serves as the methyl group donor in the transmethylation reaction such as methylation of high molecular substances in vivo of nucleic acid, protein, fat and the like which are essential for maintaining life, formation of creatine from guanidinoacetate and formation of choline from aminoethanol. Consequently, SAM is expected to be useful as a chemotherapeutant, and the therapeutic values for hepatopias, hyperdislipidemias, generalized or local arteriosclerosis, psychiatric manifestations of depressive and neurological type, degenerative arthromathies, neurological algic manifestation, disturbance of the sleeping-waking rhythm, etc., have been reported. Thus, the use of SAM in medical drugs will be developed if instability of SAM is eliminated.
From the viewpoint of practical use of SAM in medical drugs, however, SAM is very unstable even at room temperature. Therefore, it has been a serious problem that SAM alone can hardly be used as reagents for biochemical research and medical drugs. Hitherto have been known SAM salts such as the iodide, bromide, Reinecke's salt, hydrochloride and sulfate thereof, but all of these salts are unstable. For example, stability of dry SAM hydrochloride at 37.degree. C is shown in Table 1.
Table 1 ______________________________________ Storage time (day) 0 2 4 10 30 60 SAM undecomposed (%) 100 66.9 53.1 35.1 20.2 12.5 ______________________________________
The "SAM undecomposed (%)" was obtained in the following way:
A. the sample is sealed into ampoules 3 ml. in capacity, PA1 B. they are stored at a predetermined temperature for given days, PA1 C. then they are dissolved in distilled water, PA1 D. a determined amount of the solution is subjected to paper electrophoresis by employing 3% acetic acid solution, PA1 E. it is then subjected to paper chromatography in the direction at a right angle with the direction of electrophoretic migration using the developer of ethanol:acetic acid:water (65:1:34), PA1 g. these spots are extracted with 0.1 N hydrochloric acid, PA1 h. absorbances at 260 nm of the extracts are measured, and PA1 i. ratio of absorbance is calculated according to the following formula, which represents the residual ratio of SAM. The term "O.D. 260" stands for optical density at 260 nm. ##EQU1##
F. SPOTS OF SAM and those of other decomposed substances are detected by means of an ultraviolet-ray detector,
SAM p-toluenesulfonate and a double salt of SAM p-toluenesulfonate and sulfate are known as stable SAM salts (Japanese laid-open patent publication Nos. 92215/1974 and 76215/1975). SAM p-toluenesulfonate, however, has a defect in that complicated purification treatment is required in the course of production thereof.
Much research has been conducted to produce an SAM preparation having excellent stability in comparison with conventional dry SAM salts. The present inventors have found that a novel preparation comprising an SAM salt and a lithium salt has a markedly improved effect on the stability of SAM.